The overall goal of our Consortium is to elucidate the immunologic mechanisms of leading HIV-1 prophylactic vaccines and eradication strategies. Our overall hypothesis is that understanding the mechanism of action of these immunologic interventions will facilitate the clinical development of these concepts and will also lead to the next generation of vaccines and eradication strategies. Focus 1: Understanding Mechanisms of Prophylactic SIV Vaccine Efficacy. We have developed two prophylactic vaccines with distinct and potentially complementary modes of protection against highly pathogenic mucosal SIV challenges. In Focus 1, we will explore the hypothesis that Ad26/Env and CMV vector vaccines protect by distinct and potentially complementary mechanisms. The major objectives are to determine the component or components of the humoral and/or cellular immune responses responsible for the efficacy of the Ad26/Env and CMV vector vaccines, the mechanisms by which these components prevent or control/clear infection, and their potential for combinatorial enhancement of efficacy. Specific Aim 1: To determine the nature and functional characteristics of antibodies responsible for protection against acquisition of infection in monkeys vaccinated with the Ad26/Env regimen. Specific Aim 2: To determine the cell type(s) (CD8+ T cells, CD4+ T cells, NK cells) responsible for CMV vector-mediated early control and eventual clearance of SIV infection, and the immunobiologic basis of protection vs. non-protection. Specific Aim 3: To determine whether combination of an acquisition-preventing Ab-targeted vaccine and an infection-controlling/clearing cellular immunity-targeted vaccine will add or synergize in protection. Focus 2: Development of Immunologic Strategies for SIV Remission/Eradication. Functional HIV cure will likely require both viral reservoir reduction and potent, long-term anti-viral immunity such that the viral reactivation that occurs after cART cessation can be eliminated or stringently controlled over a lifetime. In Focus 2, we will explore the hypothesis that therapeutic vaccines and engineered T cells, together with sanctuary disruption and potentially latency reversal, can contribute to virus eradication strategies. Specific Aim 1: To develop vaccine vector-based strategies to elicit T cell responses able to destroy reactivating virus during cART therapy and/or control viral relapse after cART cessation. Specific Aim 2: To develop engineered autologous T cell-based strategies to destroy reactivating virus during cART therapy and facilitate control of viral relapse after cART cessation. Specific Aim 3: To determine whether 2nd generation therapeutic vaccines combined with optimized latency reversal/sanctuary therapy can enhance SIV reservoir depletion and/or control post-cART viral relapse.